Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2

J Med Chem. 2013 Jun 13;56(11):4764-85. doi: 10.1021/jm4004895. Epub 2013 May 31.

Abstract

Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.

MeSH terms

  • Administration, Oral
  • Animals
  • Antirheumatic Agents / chemical synthesis*
  • Antirheumatic Agents / chemistry
  • Antirheumatic Agents / pharmacology
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / etiology
  • Biological Availability
  • Cell Membrane Permeability
  • Collagen
  • Crystallography, X-Ray
  • Dogs
  • Haplorhini
  • Heterocyclic Compounds, 3-Ring / chemical synthesis*
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 1 / chemistry
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / chemistry
  • Madin Darby Canine Kidney Cells
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Structure
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Rats
  • Stereoisomerism

Substances

  • 4-(2-(1-hydroxyethyl)imidazo(4,5-d)pyrrolo(2,3-b)pyridin-1(6H)-yl)cyclohexanecarbonitrile
  • Antirheumatic Agents
  • Heterocyclic Compounds, 3-Ring
  • Imidazoles
  • Isoenzymes
  • Pyridines
  • Pyrroles
  • Collagen
  • Janus Kinase 1
  • Janus Kinase 2

Associated data

  • PDB/4EHZ
  • PDB/4F09
  • PDB/4IVA
  • PDB/4IVB
  • PDB/4IVC
  • PDB/4IVD